PROJECT SUMMARY/ABSTRACT Prescribing cascades occur when a healthcare provider misinterprets the side effect of a drug as a new medical condition and prescribes a second, potentially unnecessary drug therapy to address the side effect. Prescribing cascades are ?morbidity multipliers,? increasing overall symptom burden, and adversely affecting health-related quality of life and function. Patients with Alzheimer's disease are at an increased risk for prescribing cascades due to high levels of multimorbidity and polypharmacy, and the challenges and complexities of care often delivered in a manner that is not patient/caregiver-centric. The Controlling And Stopping Cascades leading to Adverse Drug Effects Study in Alzheimer's Disease (CASCADES-AD) will be a large, pragmatic trial to test a health plan-based intervention leveraging the NIH Collaboratory's Distributed Research Network, which uses the Food and Drug Administration (FDA) Sentinel Initiative infrastructure. Our overarching goal is to develop, implement, and evaluate the effect of a patient/caregiver-centered and healthcare provider educational intervention on the prevention and reversal of clinically impactful, high-priority prescribing cascades among patients with Alzheimer's disease and related dementia (ADRD). Our research hypothesis is that education on prescribing cascades among patients/caregivers and their providers can improve medication safety and reduce medication-related morbidity in patients with ADRD. Our study population, which will number 22,500, will include ADRD patients identified based on use of a medication for Alzheimer's Disease (e.g., a cholinesterase inhibitor within the prior year) who are characterized as having polypharmacy (defined as >5 active prescriptions for different agents). We will evaluate the effect of patient/caregiver and provider educational interventions (versus usual care) on the prevention or reversal of a prescribing cascade, which will serve as the primary outcome. The trial will be health plan-based, conducted in two large, national health plans. The study design will be a prospective, randomized, comparative effectiveness intervention trial with three arms: (1) a combined patient/caregiver and provider educational intervention; (2) a provider only educational intervention; and (3) usual care. The specific aims for our study are: (1) to develop a patient/caregiver-centered educational intervention, to be delivered to patients/caregivers and providers, targeting prescribing cascades among patients with ADRD; (2) to assess the impact of the intervention on the prevention and reversal of high-priority prescribing cascades among ADRD patients; (3) to evaluate the acceptability, appropriateness, and feasibility of the intervention, incorporating the perspectives of patients, caregivers, providers, and health plan leaders; and (4) to create a plan for disseminating study findings to stakeholders who might implement the intervention or make decisions about its future use. The proposed study is feasible because our partners include two large, national health plans, we will leverage an existing FDA Sentinel infrastructure, and we have a strong, multidisciplinary research team.